Untreated insomnia in those with major depressive disorder (MDD) increases risks of suicide, poor antidepressant response, and depressive relapse. Cognitive-behavioral therapy for insomnia (CBT) has established insomnia efficacy with advantages in terms of side-effects and durability of benefit over medication therapies but has slower onset of effect. However, we lack predictors of the CBT response that might help to optimally guide the choice of insomnia therapy. A key impediment in this regard is limited understanding of the therapeutic mechanisms of CBT that could provide a basis for the development of clinically useful predictors of response. This application proposes an ancillary study which aims to address this need by evaluating promising sleep EEG and genetic biomarkers of the response to CBT in individuals with insomnia comorbid with MDD. The parent study, a recently NIH-funded Phase III clinical trial, has a distinct aim of documenting that CBT enhances the depression response to antidepressant medication in 255 men and women with insomnia comorbid with MDD. The proposed study will test the hypothesis that homeostatic and arousal-related mechanisms that are reflected in sleep EEG measures and are affected by a few key genetic polymorphisms play a role in sleep disturbance in insomnia and are targeted by the components of CBT. This will be achieved by obtaining a small number of measures that will not adversely affect the parent study. Ultimately, this work could serve as the basis for the eventual development of individualized treatment of insomnia when present in the context of MDD, which could shorten the period of suffering and disability and minimize the number of patients treated with sleep medications, thus decreasing costs and side-effects and improving long-term outcome. PUBLIC HEALTH RELEVANCE: The administration of rapid and effective treatment for insomnia in those with MDD is critical in order to minimize suffering, disability, costs, and suicide risk. By evaluating potential biomarkers of the response to CBT for insomnia in MDD, the proposed study will improve our understanding of the mechanisms that play a role in sleep disturbance occurring in this setting and in the therapeutic effects of CBT. As a result, the proposed study could lead to novel insomnia therapies and, ultimately, could lead to means to increase the speed and durability of the response to antidepressant therapy and thereby result in clinically meaningful improvement in the lives of many patients with MDD and insomnia. (End of Abstract)